Article

Nonhuman primate models of Alzheimer-like cerebral proteopathy.

Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Current pharmaceutical design (Impact Factor: 4.41). 01/2012; 18(8):1159-69. DOI: 10.2174/138161212799315885
Source: PubMed

ABSTRACT Nonhuman primates are useful for the study of age-associated changes in the brain and behavior in a model that is biologically proximal to humans. The Aβ and tau proteins, two key players in the pathogenesis of Alzheimer's disease (AD), are highly homologous among primates. With age, all nonhuman primates analyzed to date develop senile (Aβ) plaques and cerebral β-amyloid angiopathy. In contrast, significant tauopathy is unusual in simians, and only humans manifest the profound tauopathy, neuronal degeneration and cognitive impairment that characterize Alzheimer's disease. Primates thus are somewhat paradoxical models of AD-like pathology; on the one hand, they are excellent models of normal aging and naturally occurring Aβ lesions, and they can be useful for testing diagnostic and therapeutic agents targeting aggregated forms of Aβ. On the other hand, the resistance of monkeys and apes to tauopathy and AD-related neurodegeneration, in the presence of substantial cerebral Aβ deposition, suggests that a comparative analysis of human and nonhuman primates could yield informative clues to the uniquely human predisposition to Alzheimer's disease.

0 Bookmarks
 · 
135 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pathological hallmarks indicative of Alzheimer's disease (AD), which are the plaques of amyloid beta1-42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers indicative of AD, had brain lesions similar to human patients suffering from senile dementia. Generating immunohistochemistry technique to biomarkers of amyloid beta1-42 and the phosphorylated tau 231, our study assessed the amyloidopathy, such as indicative to the senile plaques and cerebral amyloid angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of AD, divided equally to affected aged subject - with Memory-affected and low amyloid level, and aged with higher performance in memory and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of amyloid beta1-42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of AD. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human, the amyloids were found to deposit in the small veins and capillaries. In one of the affected individuals, phosphorylated tau was positively stained intracellularly of the neurons, indicating a possibility of an early stage of the formation of tangles. These findings add to the body of evidence of the utility of the aged cynomolgus monkeys as a spontaneous model for Alzheimer-related disease.
    Frontiers in Aging Neuroscience 11/2014; 6:313. DOI:10.3389/fnagi.2014.00313 · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Elevated amyloid-ß peptide (Aß) in brain contributes to Alzheimer's disease (AD) pathogenesis. We demonstrated the presence of exosome-associated Aß in the cerebrospinal fluid (CSF) of cynomolgus monkeys and APP transgenic mice. The levels of exosome-associated Aß notably decreased in the CSF aging animals. We also determined that neuronal exosomes, but not glial exosomes, had abundant glycosphingolipids and could capture Aß. Infusion of neuronal exosomes into brains of APP transgenic mice decreased Aß and amyloid depositions, similarly to what reported previously on neuroblastoma-derived exosomes. These findings highlight the role of neuronal exosomes in Aß clearance, and suggest that their downregulation might relate to Aß accumulation and, ultimately, the development of AD pathology. Copyright © 2014. Published by Elsevier B.V.
    FEBS Letters 11/2014; DOI:10.1016/j.febslet.2014.11.027 · 3.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimer's and prion diseases) or motor deficits (Parkinson's and related diseases).
    Frontiers in Neuroscience 01/2015; 9:64. DOI:10.3389/fnins.2015.00064

Preview

Download
1 Download
Available from